Beta1 integrin blockade overcomes doxorubicin resistance in human T-cell acute lymphoblastic leukemia

Berrazouane, Sofiane; Boisvert, Marc; Salti, Suzanne; Mourad, Walid; Al-Daccak, Reem; Barabé, Frédéric; Aoudjit, Fawzi

doi:10.1038/s41419-019-1593-2

Cited by 33 publications

(28 citation statements)

References 50 publications

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“…Also consistent with inside-out signaling, we detect talin-1 activation in CD82OE treated with daunorubicin. Additionally, the restored chemosensitivity of CD82OE cells following treatment with the α4β1 inhibitor is supported by recent findings in T-Acute Lymphoblastic Leukemia where blockade of β1 integrin sensitized xenografted leukemic cells to doxorubicin and diminished leukemic burden in the bone marrow ( 62 ). Collectively, our work supports a previously proposed concept where a tetraspanin-PKC-integrin complex is essential for signaling ( 63 ) and goes on to suggest that the level of CD82 expression serves as a modulator of signal intensity and perhaps signal duration critical for chemoresistance.…”

Section: Discussionmentioning

confidence: 59%

Tetraspanin CD82 drives acute myeloid leukemia chemoresistance by modulating protein kinase C alpha and β1 integrin activation

et al. 2020

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A principal challenge in treating acute myeloid leukemia (AML) is chemotherapy refractory disease. As such, there remains a critical need to identify key regulators of chemotherapy resistance in AML. In this study, we demonstrate that the membrane scaffold, CD82, contributes to the chemoresistant phenotype of AML. Using an RNA-seq approach, we identified the increased expression of the tetraspanin family member, CD82, in response to the chemotherapeutic, daunorubicin. Analysis of the TARGET and BEAT AML databases identifies a correlation between CD82 expression and overall survival of AML patients. Moreover, using a combination of cell lines and patient samples, we find that CD82 overexpression results in significantly reduced cell death in response to chemotherapy. Investigation of the mechanism by which CD82 promotes AML survival in response to chemotherapy identified a crucial role for enhanced protein kinase c alpha (PKCα) signaling and downstream activation of the β1 integrin. Additionally, analysis of β1 integrin clustering by super-resolution imaging demonstrates that CD82 expression promotes the formation of dense β1 integrin membrane clusters. Lastly, evaluation of survival signaling following daunorubicin treatment identified robust activation of p38 mitogen-activated protein kinase (MAPK) downstream of PKCα and β1 integrin signaling when CD82 is overexpressed. Together, these data propose a mechanism where CD82 promotes chemoresistance by increasing PKCα activation and downstream activation/clustering of β1 integrin, leading to AML cell survival via activation of p38 MAPK. These observations suggest that the CD82-PKCα signaling axis may be a potential therapeutic target for attenuating chemoresistance signaling in AML.

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Section: Discussionmentioning

confidence: 59%

Tetraspanin CD82 drives acute myeloid leukemia chemoresistance by modulating protein kinase C alpha and β1 integrin activation

et al. 2020

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“…Interestingly, α2β1 integrin but not fibronectin-binding integrins is among the adhesion molecules identified. In addition, we recently reported that the blockade of β1 integrin overcomes doxorubicin resistance in a model of T-ALL xenograft 40 . While additional studies are needed to sort out the role of each α integrin subunit in leukemia chemoresistance, our findings argue for an important role for the collagen-binding integrin α2β1 in the chemoresistance of both AML and T-ALL.…”

Section: Discussionmentioning

confidence: 99%

Cell adhesion to collagen promotes leukemia resistance to doxorubicin by reducing DNA damage through the inhibition of Rac1 activation

Naci

Berrazouane

Barabé

et al. 2019

Sci Rep

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Chemoresistance is a major hurdle in anti-cancer therapy. Growing evidence indicates that integrin-mediated cell adhesion to extracellular matrix plays a major role in chemoresistance. However, the underlying mechanisms are not fully understood. We have previously shown that the collagen-binding integrin α2β1 promoted doxorubicin resistance in acute T cell lymphoblastic leukemia (T-ALL). In this study, we found that acute myeloid leukemia (AML) cell lines also express α2β1 integrin and collagen promoted their chemoresistance as well. Furthermore, we found that high levels of α2 integrin correlate with worse overall survival in AML. Our results showed that doxorubicin-induced apoptosis in leukemic cells is associated with activation of Ras-related C3 botulinum toxin substrate 1 (Rac1) and that collagen inhibited this pathway. The protective effect of collagen is associated with the inhibition of Rac1-induced DNA damage as evaluated by the comet assay and the phosphorylated levels of histone H2AX (γ-H2AX). Together these results show that by inhibiting pro-apoptotic Rac1, α2β1 integrin can be a major pathway protecting leukemic cells from genotoxic agents and may thus represent an important therapeutic target in anti-cancer treatment.

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“…In the collagen-rich microenvironment, the activation of integrin β1 and its downstream effector JNK mediated resistance to sorafenib in triple-negative breast cancer ( Nguyen et al., 2014 ). In addition, resistance to Adriamycin in patients with T-cell acute lymphoblastic leukemia might be due to the interaction between integrin β1 and matrigel that activated the ABCC1 drug transporter ( Berrazouane et al., 2019 ). Glucocorticoid drugs are often used to reduce the toxic and side effects of chemotherapeutic drugs ( Chen et al., 2010 ).…”

Section: Integrins and Cancer Drug Resistancementioning

confidence: 99%

The Biological Functions and Clinical Applications of Integrins in Cancers

Zhang

et al. 2020

Front. Pharmacol.

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Integrins are the adhesion molecules and receptors of extracellular matrix (ECM). They mediate the interactions between cells-cells and cells-ECM. The crosstalk between cancer cells and their microenvironment triggers a variety of critical signaling cues and promotes the malignant phenotype of cancer. As a type of transmembrane protein, integrin-mediated cell adhesion is essential in regulating various biological functions of cancer cells. Recent evidence has shown that integrins present on tumor cells or tumorassociated stromal cells are involved in ECM remodeling, and as mechanotransducers sensing changes in the biophysical properties of the ECM, which contribute to cancer metastasis, stemness and drug resistance. In this review, we outline the mechanism of integrin-mediated effects on biological changes of cancers and highlight the current status of clinical treatments by targeting integrins.

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Beta1 integrin blockade overcomes doxorubicin resistance in human T-cell acute lymphoblastic leukemia

Cited by 33 publications

References 50 publications

Tetraspanin CD82 drives acute myeloid leukemia chemoresistance by modulating protein kinase C alpha and β1 integrin activation

Tetraspanin CD82 drives acute myeloid leukemia chemoresistance by modulating protein kinase C alpha and β1 integrin activation

Cell adhesion to collagen promotes leukemia resistance to doxorubicin by reducing DNA damage through the inhibition of Rac1 activation

The Biological Functions and Clinical Applications of Integrins in Cancers

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